Mechanistic and Phenotypic Characterization of Semen Amyloid Disassembler as Novel Approach to HIV Microbicide Development

The continuing spread of HIV/AIDS in people is predominantly fueled by sexual exposure to HIVcontaminated semen/seminal plasma (SP). SP harbors HIV infectivity enhancing factors that include at least two major classes of naturally occurring amyloid fibrils that promote virion attachment to cellular targets. SP also harbors a variety of pro-inflammatory factors that can indirectly facilitate HIV transmission by promoting the production of cytokines/chemokines that recruit permissive cells, enhance the translocation of HIV across the genital epithelium, and activate HIV gene transcription. These direct and indirect HIV-enhancing effects of SP could in part explain the general lack of success in developing a highly efficacious HIV microbicide. To identify inhibitors of SP's HIV-enhancing activity, we conducted a small molecule screen for disassemblers of HIV-enhancing SP amyloids. One of our top hits was gallic acid (GA), a naturally-occurring compound present in grape seeds that has previously been reported to inhibit fibril formation by amyloidogenic peptides associated with neurological diseases. We confirmed that GA inhibits the ability of both SP and SP amyloids to enhance HIV infection. Interestingly, GA has previously been reported to harbor anti-inflammatory properties, including the ability to inhibit NF-kB signaling. Together, these observations suggest that GA may inhibit SP-mediated enhancement of HIV infection by dually targeting the amyloids and the pro-inflammatory properties of SP. In this project, we investigate the mechanisms by which GA inhibits the activity of SP amyloids (Aim 1), and determine whether this compound inhibits SP-induced genital inflammation that can facilitate transmission (Aim 2). These studies will reveal whether GA would be a promising compound to develop further as a component of an HIV microbicide, and provide insights into the multiple mechanisms by which SP can enhance HIV transmission.